Keratin Expression in Podocytopathies, ANCA-Associated Vasculitis and IgA Nephropathy.

Keratins are the main components of the cell cytoskeleton of epithelial cells. Epithelial cells under stressful stimuli react by modifying their keratin expression pattern. Glomerular diseases are pathological conditions that may lead to loss of kidney function if not timely diagnosed and treated properly. This study aims to examine glomerular and tubular keratin expression in podocytopathies, ANCA-associated vasculitis, and IgA nephropathy and how this expression correlates to clinical outcomes. We included 45 patients with podocytopathies (minimal change disease and focal segmental glomerulosclerosis), ANCA-associated vasculitis, and IgA nephropathy, with or without crescentic lesions, and healthy controls. All tissues were assessed by photon microscopy and immunohistochemistry. Biopsy sections were examined for keratins 7, 8, 18, and 19 expression in the glomerular and tubulointerstitial areas separately. Moreover, we examined how keratin expression was correlated with long-term kidney function outcomes. All four studied keratins had significantly increased glomerular expression in patients with ANCA vasculitis compared to controls and MCD patients. Tubular expression of keratins 7, 8, and 19 was related to kidney outcome in all groups. Patients with crescents had higher expression of all keratins in both glomeruli and tubulointerstitium. The presence of tubular atrophy, interstitial fibrosis, mesangial hyperplasia, and interstitial inflammation did not affect keratin expression. Keratins, an abundant component of renal epithelial cells, have the potential to be featured as a biomarker for kidney function prognosis in patients with glomerular diseases.

Normal saline versus balanced crystalloids in patients with prerenal acute kidney injury and pre-existing chronic kidney disease.

INTRODUCTION: Normal saline (N/S) and Ringer's-Lactate (L/R), are administered in everyday clinical practice. Despite that, N/S increases the risk of sodium overload and hyperchloremic metabolic acidosis. In contrast, L/R has lower sodium content, significantly less chloride and contains lactates. In this study we compare the efficacy of L/R versus N/S administration in patients with prerenal acute kidney injury (AKI) and pre-established chronic kidney disease (CKD). METHODS: In this prospective open-label study we included patients with prerenal AKI and previously known CKD stage III-V without need for dialysis. Patients with other forms of AKI, hypervolemia or hyperkalemia were excluded. Patients received either N/S or L/R intravenously at a dose of 20 ml/kg body-weight/day. We studied kidney function at discharge and at 30 days, duration of hospitalization, acid-base balance and the need for dialysis. RESULTS: We studied 38 patients and 20 were treated with N/S. Kidney function improvement during hospitalization and at 30 days after discharge, was similar between the two groups. Duration of hospitalization was also similar. Anion-gap improvement as expressed with Δanion-gap between discharge and admission day was higher in those patients that received L/R in comparison to those that received N/S and pH increase (ΔpH) was slightly higher in the L/R group. No patient required dialysis. CONCLUSIONS: Administration of L/R or N/S to patients with prerenal AKI and pre-established CKD had no significant difference in short or long term kidney function but L/R showed a better profile in acid-base balance improvement and Cl- overload in comparison to N/S.

Association between PCSK9 Levels and Markers of Inflammation, Oxidative Stress, and Endothelial Dysfunction in a Population of Nondialysis Chronic Kidney Disease Patients.

Proprotein convertase subtilisin/kexin 9 (PCSK9) plays an important role in lipid metabolism while available literature regarding its involvement in the pathogenesis of atherosclerosis and in the expression of genes associated with apoptosis and inflammation is constantly increasing. Patients with chronic kidney disease (CKD) experience disproportionately increased cardiovascular morbidity and mortality due to dyslipidemia, accelerated atherosclerosis, inflammation, oxidative stress, and other risk factors. In the present cross-sectional study, we investigated the possible association of serum PCSK9 levels with markers of inflammation, oxidative stress, and endothelial damage in patients with CKD. Patients and Methods. Ninety-two patients with CKD stages II-ΙV (eGFR CKD-EPI 47.3 ± 25.7 ml/min/1.73 m2, mean age 66 years, 51 men) were included in the study. Plasma PCSK9 levels were correlated with comorbidities (arterial hypertension, diabetes mellitus, and history of cardiovascular disease), renal function indices (eGFR, proteinuria-UPR/24 h), lipid parameters (LDL-cholesterol, HDL-cholesterol, triglycerides, Lp(a), APO-A1, and APO-B), and soluble biomarkers of inflammation, oxidative stress, and endothelial damage (hs-CRP, fibrinogen, 8-epiPGF2a, ox-LDL, IL-6, TNF-α, sICAM-1, and sVCAM-1). Results. The mean plasma value of PCSK9 was 278.1 ng/ml. PCSK9 levels showed direct correlation with serum triglycerides (p = 0.03), Lp(a) (p = 0.01), and sICAM-1 levels (p = 0.03). There was no significant correlation between PCSK9 levels and indices of the renal function, other lipid profile parameters, inflammatory markers, or comorbidities. Multiple regression analysis showed a significant effect of Lp(a) on PCSK9 levels, and for each unit of higher Lp(a), an increase by 3.082 is expected (95% CI: 0.935-5.228, p = 0.006). At the same time, patients receiving statins are expected to have on average 63.8 ng/ml higher PCSK9 values compared to patients not receiving statins (95% CI: 14.6-113.5, p = 0.012). Conclusion. Plasma levels of PCSK9 in nondialysis CKD patients are correlated with endothelial dysfunction and lipid metabolism parameters. Statin intake increases PCSK9 levels significantly in this patient population. PCSK9 levels are not correlated with the severity of kidney disease. Major prospective studies are necessary to investigate the role of PCSK9 in the atherosclerotic cardiovascular outcome in CKD.

Survival of Peritoneal Membrane Function on Biocompatible Dialysis Solutions in a Peritoneal Dialysis Cohort Assessed by a Novel Test.

BACKGROUND: Longitudinal surveillance of peritoneal membrane function is crucial in defining patients with a risk of ultrafiltration failure. Long PD is associated with increased low molecular weight solute transport and decreased ultrafiltration and free water transport. Classic PET test only provides information about low molecular solute transport, and the vast majority of longitudinal studies are based on this test and include patients using conventional dialysates. Our aim was to prospectively analyze longitudinal data on peritoneal function in patients on biocompatible solutions using a novel test. METHODS: Membrane function data were collected based on uni-PET (a combination of modified and mini PET). A total of 85 patients (age 61.1 ± 15.1 years) with at least one test/year were included. RESULTS: The median follow up was 36 months (21.3, 67.2). A total of 219 PETs were performed. One-way repeated measures ANOVA showed that there were no statistically significant differences over time in ultrafiltration, free water transport, ultrafiltration through small pores, sodium removal, D/D0 and D/PCre in repeated PET-tests. Twenty-three tests revealed ultrafiltration failure in 16 (18.8%) patients. Those patients were longer on PD, had higher D/P creatinine ratios, lower ultrafiltration at one hour with lower free water transport and higher urine volume at baseline. Multivariate analysis revealed that the variation of ultrafiltration over repeated PET-tests independently correlated only with D/Pcreatinine, free water transport and ultrafiltration through small pores. CONCLUSIONS: Uni-PET is a combination of two tests that provides more information on the function of the membrane compared with PET. Our study on a PD cohort using only biocompatible solutions revealed that function membrane parameters remained stable over a long time. Ultrafiltration failure was correlated with increased D/P creatinine and decreased free water transport and ultrafiltration through small pores.

Case Report: Kidney Transplantation in a Patient With Acquired Agammaglobulinemia and SLE. Issues and Challenges.

Lupus nephritis in the context of Systemic Lupus Erythematosus (SLE) is characterized by an unpredicted course with remissions and flare-ups. Among others, it remains a significant cause of end-stage kidney disease (ESKD) in relatively young patients. Therapeutic regimens with newer immunosuppressive agents have been introduced in order to control SLE clinical manifestations more efficiently and limit organ damage induced by immune complex formation and sustained inflammation. Treatment is usually long-term, and the cumulative impact of immunosuppression is expressed through the increased frequency of infections and neoplasms. However, if the observed immunity dysregulation is secondary and pharmaceutically induced or there is a pre-existing, primary immunodeficiency that shares common pathogenetic pathways with SLE's autoimmunity is not always clear. Herein, we present the case of a 39-year-old woman, that reached ESKD due to lupus nephritis. After an upper respiratory cytomegalovirus (CMV) infection and concomitant CMV reactivations the investigation revealed significant immunodeficiency. Not long after the initiation of intravenous immunoglobulin (IVIG) administration, patient received a cadaveric kidney transplant. IVIG was continued along with standard immunosuppression so that both recurrent infections and allograft rejection are avoided. Patient is closely monitored, and her post-transplant course is remarkably satisfying so far. ESKD patients with immunodeficiency syndromes should not be excluded by definition from kidney transplantation.

Hypertension in Chronic Kidney Disease: Novel Insights.

Management of arterial hypertension in patients with chronic kidney disease (CKD) remains a major challenge due to its high prevalence and associations with cardiovascular disease (CVD) and CKD progression. Several clinical trials and meta-analyses have demonstrated that aggressive treatment of hypertension in patients with and without CKD lowers the risk of CVD and all-cause mortality, nevertheless the effects of blood pressure (BP) lowering in terms of renal protection or harm remain controversial. Both home and ambulatory BP estimation have shown that patients with CKD display abnormal BP patterns outside of the office and further investigation is required, so as to compare the association of ambulatory versus office BP measurements with hard outcomes and adjust treatment strategies accordingly. Although renin-angiotensin system blockade appears to be beneficial in patients with advanced CKD, especially in the setting of proteinuria, discontinuation of renin-angiotensin system inhibition should be considered in the setting of frequent episodes of acute kidney injury or hypotension while awaiting the results of ongoing trials. In light of the new evidence in favor of renal denervation in arterial hypertension, the indications and benefits of its application in individuals with CKD need to be clarified by future studies. Moreover, the clinical utility of the novel players in the pathophysiology of arterial hypertension and CKD, such as microRNAs and the gut microbiota, either as markers of disease or as therapeutic targets, remains a subject of intensive research.

Histological grading in primary membranous nephropathy is essential for clinical management and predicts outcome of patients.

AIMS: Diagnosis of primary membranous nephropathy (PMN) is mainly based on immunofluorescence/immunohistochemistry findings. However, assessment of specific features on optical microscopy can help to estimate the severity of the disease, guide treatment and predict the response. The aim of this study was to identify, classify and grade the precise histological findings in PMN to predict renal function outcome and guide treatment. METHODS AND RESULTS: Histological parameters, including focal segmental sclerosis (FSGS), tubular atrophy (TA), interstitial fibrosis (IF) and vascular hyalinosis (VH), were re-evaluated in 752 patients with PMN. Their predictive value was estimated separately, and also in a combination score (FSTIV) graded from 0 to 4. Finally, the impact of histology was assessed in the response to immunosuppressive treatment. Mean age of patients was 53.3 (15-85) years and most presented with nephrotic syndrome. FSGS was present in 32% and VH in 51% of the patients, while TA and IF were graded as stage ≥1 in 52% and 51.4%, respectively. The follow-up period was 122.3 (112-376) months. FSGS, TA and IF and VH were associated with impaired renal function at diagnosis (P = 0.02, P < 0.0001, P = 0.001 and P = 0.02, respectively) and at the end of follow-up (P = 0.004, P < 0.0001, P < 0.0001 and P = 0.04, respectively). In multiple regression and binary logistic analysis, the presence of FSGS and degree of TA were the most significant parameters predicting renal function outcome, defined either by eGFR (end), FSGS (r = 0.6, P < 0.0001) and TA (r = 0.6, P < 0.0001), or by the endpoint of >50% eGFR reduction, FSGS (P = 0.001) and TA (P = 0.02). Also, patients presented with FSGS, IF, VH and/or with FSTIV > 1 could benefit from immunosuppression, regardless of clinical presentation. CONCLUSIONS: The presence and degree of four histological indices, FSGS, VH, TA and IF, assessed separately or in combination, and FSTIV score not only predict renal function outcome after long-term follow-up, but can also help in the choice of appropriate treatment. Decisions concerning immunosuppressive treatment can be guided by pathology regardless of clinical findings.

Oxidative Stress and the Kidney in the Space Environment.

In space, the special conditions of hypogravity and exposure to cosmic radiation have substantial differences compared to terrestrial circumstances, and a multidimensional impact on the human body and human organ functions. Cosmic radiation provokes cellular and gene damage, and the generation of reactive oxygen species (ROS), leading to a dysregulation in the oxidants⁻antioxidants balance, and to the inflammatory response. Other practical factors contributing to these dysregulations in space environment include increased bone resorption, impaired anabolic response, and even difficulties in detecting oxidative stress in blood and urine samples. Enhanced oxidative stress affects mitochondrial and endothelial functions, contributes to reduced natriuresis and the development of hypertension, and may play an additive role in the formation of kidney stones. Finally, the composition of urine protein excretion is significantly altered, depicting possible tubular dysfunction.

Oxidative Stress and Acute Kidney Injury in Critical Illness: Pathophysiologic Mechanisms-Biomarkers-Interventions, and Future Perspectives.

Acute kidney injury (AKI) is a multifactorial entity that occurs in a variety of clinical settings. Although AKI is not a usual reason for intensive care unit (ICU) admission, it often complicates critically ill patients' clinical course requiring renal replacement therapy progressing sometimes to end-stage renal disease and increasing mortality. The causes of AKI in the group of ICU patients are further complicated from damaged metabolic state, systemic inflammation, sepsis, and hemodynamic dysregulations, leading to an imbalance that generates oxidative stress response. Abundant experimental and to a less extent clinical data support the important role of oxidative stress-related mechanisms in the injury phase of AKI. The purpose of this article is to present the main pathophysiologic mechanisms of AKI in ICU patients focusing on the different aspects of oxidative stress generation, the available evidence of interventional measures for AKI prevention, biomarkers used in a clinical setting, and future perspectives in oxidative stress regulation.

"Diabetic nephropathy" in a non-diabetic patient.

Kimmelstiel and Wilson originally described nodular glomerulosclerosis as the pathognomonic lesion of diabetic nephropathy. Nevertheless, nodular glomerulosclerosis pattern can rarely occur in non-diabetic patients. In such cases, the differential diagnosis includes membranoproliferative glomerulonephritis, light or heavy chain deposition disease, amyloidosis, fibrillary and immunotactoid glomerulonephritis and chronic hypoxic or ischemic conditions. In cases that the above entities cannot be proven, the term idiopathic nodular glomerulosclerosis is given. Here, we report a case of a male patient with renal failure stage IV and non-nephrotic range proteinuria. He had a history of heavy smoking and hypertension. The kidney biopsy revealed diabetic-like lesions. However, there was no evidence of glucose impairment despite the thorough work-up at the biopsy time and thereafter. The laboratory data and the electron microscopy of the specimen could not prove any other cause of nodular glomerulosclerosis, and the final diagnosis was idiopathic nodular glomerulosclerosis. Moreover, we focus on the pathological differential diagnosis and work-up.